title: Direct regulation of complex I  by mitochondrial MEF2D is disrupted  in a mouse model of Parkinson disease  and in human patients.
abstract: The transcription factors in the myocyte enhancer factor 2 (MEF2) family play important roles in cell survival by regulating nuclear gene expression. Here, we report that MEF2D is present in rodent neuronal mitochondria, where it can regulate the expression of a gene encoded within mitochondrial DNA (mtDNA). Immunocytochemical, immunoelectron microscopic, and biochemical analyses of rodent neuronal cells showed that a portion of MEF2D was targeted to mitochondria via an N-terminal motif and the chaperone protein mitochondrial heat shock protein 70 (mtHsp70). MEF2D bound to a MEF2 consensus site in the region of the mtDNA that contained the gene NADH dehydrogenase 6 (ND6), which encodes an essential component of the complex I enzyme of the oxidative phosphorylation system; MEF2D binding induced ND6 transcription. Blocking MEF2D function specifically in mitochondria decreased complex I activity, increased cellular H(2)O(2) level, reduced ATP production, and sensitized neurons to stress-induced death. Toxins known to affect complex I preferentially disrupted MEF2D function in a mouse model of Parkinson disease (PD). In addition, mitochondrial MEF2D and ND6 levels were decreased in postmortem brain samples of patients with PD compared with age-matched controls. Thus, direct regulation of complex I by mitochondrial MEF2D underlies its neuroprotective effects, and dysregulation of this pathway may contribute to PD.
authors.affiliation: Department of Pharmacology, Rollins School of Public Health, Atlanta, Georgia, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: She
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Kennie
authors.initials: K
authors.lastname: Shepherd
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Miller
authors.forename: Claudia
authors.initials: C
authors.lastname: Testa
authors.forename: Zixu
authors.initials: Z
authors.lastname: Mao
mesh_terms: D000368:Aged; D020816:Amino Acid Motifs; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000737:chemistry; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D026161:MADS Domain Proteins / Q000378:metabolism / Q000502:physiology*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D004272:DNA, Mitochondrial; D018840:HSP70 Heat-Shock Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; D042967:Electron Transport Complex I; D010100:Oxygen